Cardiovascular diseases (CVD) and infectious diseases are the leading and second causes of death respectively in chronic hemodialysis (HD) patients. Traditional Framingham factors do not appear to sufficiently account for the CVD risks in this population. We therefore propose to explore the role of vitamin D deficiency as a non-traditional CVD risk factor. 25-hydroxyvitamin D (25(OH)D) is converted to the active form, 1,25-dihydroxyvitamin D (1,25(OH)2 D), by the enzyme 1-1-hydroxylase in the kidney. The discoveries that many extra-renal tissues also possess the 1-1-hydroxylase enzyme and vitamin D receptors have provided new insights into the important physiologic autocrine/paracrine roles of vitamin D in various organs, that are dependent on the availability of 25(OH)D from the circulating plasma. Accordingly, epidemiologic data have related 25(OH)D deficiency to CVD and infectious diseases in the non-uremic population. Information in the HD population in this regard is scarce and will constitute the main goal of the present application. We propose to use the stored serum samples and data base from the completed NIDDK-sponsored HEMO Study to examine the relationship between serum vitamin D levels, inflammatory markers and clinical events in chronic HD patients. The objectives of this application are: (1) To measure levels of 25(OH)D, 1,25(OH)2D, Interleukin-6 (IL-6), and high-sensitivity C-reactive protein (hs- CRP) in predialysis serum samples collected at baseline and during annual follow-up from chronic HD patients randomized in the HEMO Study. A total of 1228, 1188, 823, 552, 381 and 231 samples collected respectively at the baseline and in follow-up years 1-5 will be assayed (Aim 1). (2) To examine the relationship of serum 25(OH)D levels with cardiac composite outcomes and infectious composite outcomes during follow-up, after statistical adjustment for 1,25(OH)2D and known risk factors for these events (Aim 2 and Aim 3). (3) To examine whether the relationships of cardiac events with lower baseline and follow-up serum 25(OH)D levels are attenuated with statistical adjustment for serum levels of IL-6 and hs-CRP. Positive results of this analysis would suggest that these inflammatory markers are in the causal pathways of the clinical cardiac consequences of 25(OH)D deficiency (Aim 4). Understanding the relationship between serum 25(OH)D levels with clinical outcomes will yield interesting scientific information and have important diagnosti an therapeutic implications for chronic HD patients. PUBLIC HEALTH RELEVANCE: chronic kidney disease is very common in the U.S. but has been generally under-recognized in the last few decades. Patients with advanced kidney disease, especially those requiring chronic hemodialysis, have very high death rates due to heart diseases and infections. The reasons for these high risks are unclear. This research proposal will focus on another epidemic in dialysis patients, namely, vitamin D deficiency, which may be a contributing cause to their heart diseases and infections. Although vitamin D deficiency has long been known to cause bone diseases, evidence is rapidly accumulating in the general U.S. population showing that chronic vitamin D deficiency also causes hypertension, diabetes, myocardial infarction, heart failure, infections and disorder of the immune system, all of which are also very common medical complications in dialysis patients. This application will examine if vitamin D deficiency can indeed be linked to heart diseases and infections in chronic dialysis patients. If the results are positive, it would help to explain why these patients are at such high risks for heart diseases and infections. In addition, it would provide a sound basis for a large clinical trial of vitamin D supplementation to improve the very poor clinical outcomes of dialysis patients.